UHRF2 mediates resistance to DNA methylation reprogramming in primordial germ cells
In mammals, primordial germ cells (PGCs) undergo global erasure of DNA methylation with delayed demethylation of germline genes and selective retention of DNA methylation at evolutionarily young retrotransposons. However, the molecular mechanisms of persistent DNA methylation in PGCs remain unclear. Here we report that resistance to DNA methylation reprogramming in PGCs requires UHRF2, the paralog of the DNMT1 cofactor UHRF1. PGCs from Uhrf2 knock-out mice show loss of retrotransposon DNA methylation, while DNA methylation is unaffected in somatic cells. This is not associated with changes in the expression of retrotransposons in E13.5 PGCs, indicating that other mechanisms compensate for retrotransposon control at this stage. Furthermore, Uhrf2-deficient PGCs show precocious demethylation of germline genes and overexpress meiotic genes in females. Subsequently, Uhrf2-deficient mice show impaired oocyte development and female-specific reduced fertility, as well as incomplete remethylation of retrotransposons during spermatogenesis. These findings reveal a crucial function for the UHRF1 paralog UHRF2 in controlling DNA methylation in the germline.
Authors
- Ambre Bender (ORCID: https://orcid.org/0000-0001-5872-4747)
- Norbert B. Ghyselinck (ORCID: https://orcid.org/0000-0003-4042-6818)
- Michaël Weber (ORCID: https://orcid.org/0000-0003-3484-5821)
- Michaël Dumas (ORCID: https://orcid.org/0000-0001-8527-7006)
- Max Greenberg (ORCID: https://orcid.org/0000-0001-9935-8763)
- Muriel Klopfenstein
- Marion Morel (ORCID: https://orcid.org/0000-0002-1439-5360)
- Déborah Bourc’his (ORCID: https://orcid.org/0000-0001-9499-7291)
- Naël Osmani (ORCID: https://orcid.org/0000-0003-1195-753X)
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université Paris Cité (FR)
- Université Paris Sciences et Lettres (FR)
- Institut de génétique et de biologie moléculaire et cellulaire (FR)
- La Ligue Contre le Cancer (FR)
- Institut Jacques Monod (FR)
- Biotechnologie et Signalisation Cellulaire (FR)
- Génétique et biologie du développement (FR)
- Université de Strasbourg (FR)
- Institut Curie (FR)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-09
- DOI
- https://doi.org/10.1038/s41467-025-61954-0
- Citations
- 1
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Fondation pour la Recherche Médicale
- Université de Strasbourg
- Centre National de la Recherche Scientifique